Compositions and methods for altering second messenger signaling

• US 10,131,686 B2
• Filed: 12/08/2017
• Issued: 11/20/2018
• Est. Priority Date: 04/29/2013
• Status: Active Grant

• Current Assignee: Bond University, Memorial Sloan-Kettering Cancer Center, Rockefeller University, Rutgers University
• Original Assignee: Bond University, Memorial Sloan-Kettering Cancer Center, Rockefeller University, Rutgers University
• Inventors: Patel, Dinshaw J., Tuschl, Thomas, Ascano, Jr., Manuel, Wu, Yang, Liu, Yizhou, Barchet, Winfried, Hartmann, Gunther, Zillinger, Thomas, Jones, Roger, Gaffney, Barbara L., Gao, Pu
• Primary Examiner(s): Murray, Jeffrey H
• Application Number:
  US15/836,763
• Publication Number:
  US 20180127454A1
• Time in Patent Office: 347 Days
• Field of Search: 514 75, 544244
• CPC Class Codes: A61K 31/522 having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• CPC Class Codes: A61K 47/55 the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
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• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
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• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
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• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/24 Antidepressants
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• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/02 : Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 3/06 : Antihyperlipidemics
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
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• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/04 : Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
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• CPC Class Codes: C07F 9/65746 : the molecule containing more than one cyclic phosphorus atom
• CPC Class Codes: C07H 21/00 : Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
• CPC Class Codes: C12Q 1/485 : involving kinase
• CPC Class Codes: C12Y 207/07 : Nucleotidyltransferases (2.7.7)
• CPC Class Codes: G01N 2500/04 : Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)
• CPC Class Codes: G01N 2500/10 : involving cells
• CPC Class Codes: G06V 20/698 : Matching; Classification
• CPC Class Codes: G16B 15/00 : ICT specially adapted for analysing two-dimensional or three-dimensional molecular structures, e.g. structural or functional relations or structure alignment
• CPC Class Codes: G16B 20/00 : ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations
• CPC Class Codes: G16B 20/30 : Detection of binding sites or motifs
• CPC Class Codes: G16B 20/50 : Mutagenesis

Abstract

The invention relates to compositions, methods, kits, and assays related to the use and/or exploitation of isomers of cGAMP as well as the structure of the enzyme cGAS.

Claims

1. A compound of Formula I:

2. The compound of claim 1, wherein Ring A is

3. The compound of claim 1, wherein Ring B is

4. The compound of claim 1, wherein Ring B

5. The compound of claim 1, wherein each X¹ and X² is —

N—

.

6. The compound of claim 1, wherein X^a and X^b are —

O—

.

7. The compound of claim 1, wherein X^c and X^d are both sulfur.

8. The compound of claim 1, wherein R¹ is selected from the group consisting of hydrogen, halogen, and —

OH.

9. The compound of claim 1, wherein R² is selected from the group consisting of hydrogen, halogen, and —

OH.

10. The compound of claim 1, wherein each of R³, R⁵, and R⁷ is hydrogen.

11. The compound of claim 1, wherein R⁴ and R⁶ are each —

NH₂.

12. The compound of claim 1, wherein R¹⁰ and R¹¹ are each hydrogen.

13. The compound of claim 1, wherein the compound is of formula I-a:

14. The compound of claim 1, wherein the compound is of formula III, VII, or IX:

15. The compound of claim 14, wherein X^c and X^d are both sulfur.

16. The compound of claim 14, wherein R¹ is selected from the group consisting of hydrogen, halogen, and —

OH.

17. The compound of claim 14, wherein R² is selected from the group consisting of hydrogen, halogen, and —

OH.

18. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

19. A method for treatment or prevention of cancer, comprising administering to a subject in need thereof the pharmaceutical composition of claim 18.